The hypothalamic-pituitary adrenal (HPA) axis is a centrally controlled neuroendocrine system that mediates adaptive, biobehavioral responses to psychosocial stress. It also links stress to diseases as divergent as depression and AIDS, through unclear mechanisms. Clarifying mechanisms requires more precise understanding of specific activators and modulators of this system. Surprisingly, expected activators that generate high distress, like phobic fear or a panic attack, do not always trigger release of HPA hormones (ACTH or cortisol). Animal data show that novelty, control, and social milieu can modulate HPA activation, but these factors are little studied in humans. The goal of this project is to explore the role of contextual factors (e.g., novelty, control) in normal human HPA axis activity and their relevance to a more complete understanding of HPA axis dysregulation in psychiatric disorders, through three complementary experiments. The Trier Social Stress Test (TSST) is a "social evaluative threat" laboratory model for studying ACTH and cortisol responses to psychosocial stress. The first study will test the hypothesis that sense of control is more important than level of perceived threat in shaping hormonal responses - i.e., providing access to control/coping responses, even when control is not utilized and subjectively experienced anxiety is not reduced, will block the cortisol response usually produced by the social evaluative threat of the TSST. The second study will use a model of fear sensitivity to non-social threats (phobias), to test the hypothesis that sense of control is more salient to cortisol release than fear itself. The third study will apply initial findings to a psychiatric disorder (panic disorder) in which HPA axis dysregulation has been considered to be etiologically central and test the hypothesis that HPA axis abnormalities can be created by hypersensitivity to contextual cues, suggesting a supra-hypothalamic source for HPA axis dysregulation in this disorder. These experiments will advance understanding of normal HPA axis functioning and demonstrate how this understanding can be used to hone in on the location of disrupted circuitry in a psychiatric disorder with suspected HPA axis dysregulation. Follow-up neuroimaging studies using these paradigms will trace the neural pathways through which higher neural circuits (supra-amygdaloid and supra-hypothalamic) modulate lower, automatic emotional processors. Ultimately, these efforts will help us better understand the role of stress in disease and develop improved methods for modulating its negative effects.